This invention provides an apparatus and associated method for mixing materials, which afford exquisite control over mixing in a wide range of applications. The range extends from heavy duty agitation for preparation of concrete to delicate and precise mixing required for the pre for the preparation of pharmaceuticals and the processing of biological cultures in which living organisms must remain viable through the procedure.
The mixing of fluids involves the creation of fluid motion or agitation resulting in the uniform distribution of either heterogeneous or homogeneous starting materials that form an output product. Mixing processes are called upon to effect the uniform distribution of: miscible fluids such as ink in water; immiscible fluids such as the emulsification of oil in water; of particulate matter such as the suspension of pigment particles in a carrier fluid; mixtures of dry materials with fluids such as sand, cement and water; the chemical ingredients of oral-dosage-form pharmaceuticals; and biological specimens, such as bacteria, while growing in a nurturing media without incurring physical damage.
Mixing may be done in a variety of ways; either a rotating impeller(s) mounted onto a shaft immersed in the fluid mixture agitate(s) the fluid and/or solid materials to be mixed, or a translating perforated plate does the agitation, or the vessel itself containing the materials is agitated, shaken or vibrated. Mixing may be continuous (as when a rotating impeller is used or the containing vessel is vibrated) or intermittent as when the drive mechanism starts and stops in one or several directions.
With any conventional rotational motor, the frequency, generally measured in revolutions per minute (RPM), can be set at any value within a suitable range for different uses, but it is quite rare in fact that the RPM is varied rapidly during use. Mixers using conventional motors are set usually at one RPM, at which they run for the duration of the mixing. Sometimes the RPM may be varied during mixing, but it is either continuously changed slowly or incremented only a few times. The RPM is not usually incremented continuously or over a large number of RPM changes.
With a conventional vibrational mixer, the amplitude can be varied within very narrow limits, and the frequency is generally set at the frequency of the AC power source. Even when using a motor controller with frequency control, the vibrational frequency of a conventional vibrational mixer can be varied only within relatively narrow limits.
When biological tissue is cultivated, all cells must stay suspended in the nutrient broth; that is, the cells should not sediment to the bottom of the vessel in which they are cultivated. However, in agitating living cells so as to minimize sedimentation, the mechanical effect of the agitator should not compromise the integrity of the cells. In the case of rotating agitators, quite often the culture medium creates a turbulent vortex into which the cells are sucked. Under the turbulent vortex conditions, the cells are at greater risk of being mechanically damaged and the continuous supply of oxygen to the cells is not consistently assured.
The present invention provides a vibration mixer driven by an electronically controllable motor, adapted so as to allow virtually unlimited control of the mixing process. To accomplish this, the present invention builds on the developments of U.S. Pat. No. 5,033,321 issued to D. Gerson (the xe2x80x9cGerson Patentxe2x80x9d), hereby incorporated by reference in its entirety.
The Gerson patent concerns an apparatus and method for measuring the degree or rate of mixing during the mixing process. The Gerson patent discloses a closed-loop feedback system for use with then available vibration mixers. The Gerson system comprises a sensor that detects certain physical or chemical parameters that indicate the degree of mixing, i.e., the degree of turbulence, which in turn provides a quantitative measure of the degree of homogeneity of the mixed fluid. Through a feedback loop of testing when the key parameters achieve certain values, the Gerson sensor aids in determining that the mixing has achieved a desired level of homogeneity. In developing the feedback system, the Gerson patent reveals that optimal mixing results are achieved by simultaneously adjusting both the amplitude and the frequency of the vibration mixing device. However, the heretofore available vibration mixers have not readily allowed the simultaneous and independent adjustment of both the amplitude and the frequency of vibration in order to take advantage of the Gerson technology. The heretofore available vibration mixers have been restricted to a narrow range of both frequencies and amplitudes. Thus, the present invention provides a vibration mixer that can take ready advantage of the Gerson technology.
In accordance with the present invention, a vibration mixer comprises a motor, controlled by an electronic controller, and an agitator, driven by the motor to agitate a fluid to be mixed; this fluid is sometimes hereinafter called the xe2x80x9cmixant.xe2x80x9d The mixant, which may be entirely liquid or may contain particulates with or without liquid, or foam, generally starts out heterogeneous and is intended to be made at least somewhat more homogeneous. Alternatively, in other embodiments, the mixant is a fluid that is to be agitated in order to maintain a desired state of homogeneity or to aerate or circulate nutrients in a biological fermenter, or the like.
The present invention permits independent and simultaneous adjustment of both the frequency and the amplitude of a vibrational mixer thereby allowing almost unlimited control of the mixing process. Additionally, this invention permits the adjustment of the vibrational rate from extremely low frequencies to frequencies in the order of 10 Hz or greater. Furthermore, this invention permits the adjustment of the amplitude of vibrational travel from micrometers to meters, depending on the size and scale of the mixer vessel. Additionally, this invention permits the adjustment of the waveform of the vibrational mixing to sinusoidal, pulsatile, square-wave, or to a complex waveform, any of which can be programmed into the control unit.
There are numerous alternative embodiments of the vibration mixer of the present invention, any and all of which can be selected depending on the user""s needs and the mixing process being performed. One embodiment is a configuration to provide up and down (or alternatively a horizontal back and forth) oscillatory motion of the agitator to bring about the desired mixing. In still another embodiment the mixer may be configured to provide discrete steps in rotational motion to effect the desired mixing.
Where the motor provides rotational motion, as by a stepper motor, the rotational velocity, or instantaneous RPM, may be caused to change rapidly many times during each revolution or up-and-down oscillation. In this invention, an operator may program the changes at will RPM so as to create any step-by-step pattern desired. In comparison to a conventional rotational mixer, the instantaneous RPM can be varied in very small intervals of time and rotation, such that one rotational step can be fast or slow, or forwards or backwards, within broad limits.
In accordance with the present invention, the motor may be a linear motor, a stepper motor or a DC continuous motor. Selection of the preferred motor may depend on the agitating profile which may include, for example, the speed, the direction, the continuity or intermittency of agitation, and the amount of energy required to agitate the mixant to the degree appropriate to the task.
The agitator may be, for example, an impeller driven in a circular motion, a perforated stirrer plate moved translationally, or some other means for agitating the mixant. As it relates to a vessel in which the mixant is contained, such an impeller or stirrer plate may have a diameter almost equal to that of the vessel or extend only a small percentage of the cross-sectional area of the vessel. Optionally, several vessels may be mounted on a common support and the mixants therein simultaneously agitated by agitators ganged by connecting bars driven by a single motor.
The vessel may have the diameter of a small glass beaker or a stainless steel vat large enough to accommodate substantial quantities of fluids, e.g. in industrial processes. In accordance with the present invention, the vessel may optionally be sealed, for example, in the event that a toxic material is being processed, or pressure or vacuum is desired during the mixing process.
The controller provides continuous control of the agitation of the mixant, keeping it constant or varying in time, depending on the desired result. The controller comprises an electronic control unit which generates low level control signals and a motor drive unit communicating therewith which provides high level energy to power the motor in accordance with the control signals. Also, the motor drive unit receives position information from the motor and communicates such information to the control unit. The rate of repetitive, i.e. vibrational, motion of the agitator, i.e. rotation or reciprocation, can be programmed within a wide range, e.g. in some embodiments from 0.01 to 10 Hz, or in other embodiments from 0.1 to 6 Hz.
The motion provided by the motor, as powered by the motor drive unit, provides the variations sought by the technician based upon experience or experiment.
In certain embodiments of the invention, a sensor is provided to the vibration mixer to sense a variable related to the degree of mixing of the mixant. As disclosed in the Gerson patent, the sensor sends a signal to a meter device, which in turn sends an input signal, derived from the pressure fluctuation spectra or other measured spectra, to the electronic controller. This input signal to the controller is indicative of fluid motion that is, of fluid turbulence, and provides a feedback loop mechanism by which to electronically vary the driving motor of the mixer, thereby promoting an optimum mixing result in the mixant. By providing a mixer that can continuously adjust to changes to the frequency and the amplitude of the mixing motion as directed by the input signal of the controller to the driving motor of the mixer, the present invention can obtain a desired mixing result in the mixant.
One embodiment of the invention provides agitation of a mixant in a vessel by an agitator. The agitator is electrically powered to produce reciprocating and/or rotational motion in controlled increments, thus generating mixing forces in the fluid contained in the vessel. The motor is adapted to move in steps and moves the agitator in a controlled, incremental manner. It may be a stepper motor, a linear motor, or a DC motor. The motor is directly connected to the agitator via a shaft that extends into the fluid to be mixed. In another embodiment, the agitator is indirectly coupled to the motor by a mechanical element that converts rotational movement to reciprocating movement, or vice versa.
A controller comprises a control unit providing frequency control and amplitude control and further comprises a motor drive unit. The controller drives the motor. The controller may be automatically adjusted by signals based upon feedback information from a sensor in the mixing vessel.
In one embodiment of the invention, the agitator comprises a stirrer plate with a plurality of frusto-conical orifices therein, the plate being perpendicularly attached to the shaft.
In some embodiments of the invention, a stepper motor having a rotating shaft, attached to a low-friction rotation-to-reciprocation converter, by means of a ball-bearing spindle, provides motion to a shaft connected to the agitator. The stepper motor may be synchronous or non-synchronous. Such embodiments are most effective for vessels of 2 to 30 liters.
In other embodiments, electrically powered means for reciprocating the shaft in a controlled manner comprises a linear motor. Such a motor provides reciprocating motion directly to the shaft on which the agitator is mounted, without requiring a ball-bearing spindle as mentioned above. Such embodiments are most effective for vessels of 2 to 300 liters. In still another embodiment, the electrically powered means comprises a DC continuous motor. Such embodiments are most effective for volumes greater than about 300 liters.
The present invention may further comprise a sensor located in the mixing vessel, providing input to a means for determining the degree of mixing of the fluid in the vessel. These elements generate a power spectrum signal indicative of certain physical parameters in the vessel, which is then processed by the control unit to provide adjustment to the frequency and amplitude of the agitation.
Where it is desired to hermetically seal the vessel, e.g. due to toxicity or dangerous emissions, the system may additionally comprise a sealing membrane secured to the shaft, comprising a bellows to prevent leakage around the mixing shaft. In any of these mechanical configurations wherein a stepper motor is used, it is envisioned that the stepper motor controller would be capable of providing appropriate signals to the stepper motor to independently adjust the frequency (e.g. in a range of 0.01 to 5 or even 10 Hz) and the amplitude of mixing within the desired range. The amplitude and the frequency may be desirably displayed digitally and provided in a manner to be recorded or read by a computer for subsequent review.
It is envisioned that the stepper motor controller is part of a feedback loop, such as described in the Gerson Patent to maintain a constant or varying mixing signal, to provide useful mixing in the mixant. Such devices are available from Rxc3xcitten Engineering, Stxc3xa4fa, Switzerland, as MIXMETER(trademark) systems.
Although, for smaller vessels, a stepper motor may effectuate the motion of the agitator; for larger sized vessels, other motors may be used to provide other motion and for a longer agitator. Such other motor be a linear motion motor. Alternatively a DC motor may be used when high power input is needed, for example, in large-scale applications. With electronic control of an appropriate motor, the motion can be driven in any desired cyclic waveform, for example having amplitudes in excess of 1200 mm and speed up to about 10 Hz (cycles per second) with vessel size being the sole limit.
The agitator element of the present invention may be any known impeller or plunger that would be expected to give useful results with the mixant in a vessel of the size to be used with the vibration mixer of the present invention. In the case of the stepper motor providing translational motion in the mixing vessel, a low-friction ball-bearing spindle is driven to provide the desired movement of the agitator.
The agitator, for example, may comprise a stirrer plate with frusto-conical holes, the holes having axes perpendicular to the direction of motion. The agitator disclosed hereinbelow is also an invention.
In certain embodiments using a stepper motor, the plate is moved up and down by the stepper motor in conjunction with a ball-bearing spindle. The conical holes can be arranged to taper from the bottom to the top, from top to bottom or both. One or several plates can be mounted on the agitator shaft, one above the other, movable or fixed in place.
The holes in the stirrer plate, no matter what their shape may have their edges rounded. For use with biological cultures, this is essential to preserve the integrity of the cell culture by reducing turbulence and avoiding rigorous forces on the cultures. The holes in the stirrer plate can have any of various characteristics of diameter, shape, and number, depending on the application. The diameter of the stirrer plate is preferably from 20% to 70% of the mixing vessel diameter but may be any size smaller than the diameter of the vessel, depending on the mixant to be mixed. Also, the amplitude of agitator motion may be from 1 mm to several hundred mm, depending on the container size. The amplitude of agitator motion may be adjustable over a wide range, limited only by the vessel dimension.
When used for sterile or poisonous or pathological media or under vacuum conditions, the vessel and mixer can be sealed. In sealed applications, for low amplitudes, less than 4-5 mm, a sealing membrane made of flexible material suitable to contain the mixant can be used. When high pressure is applicable in the mixing vessel, a counter pressure from outside the sealed application can be applied to provide pressure compensation on the sealing membrane. For agitator amplitudes larger than 4-5 mm, bellows are suitable. The bellows is designed to accommodate the pressure inside the mixing vessel, the amplitude and the frequency of motion of the agitator for long time periods without material failure due to fatigue, and for cleaning in place (xe2x80x9cCIPxe2x80x9d).
The use of a MIXMETER(trademark) system in the feedback loop provides an optimized application for stirring processes that have to run and be documented as batch processes with consistent results. Thus, the same results will be achieved for the same grade of turbulence under increasing or decreasing filling volume with the mixing vessel.
A further embodiment of the invention involves the mixing of the contents of two, three or more vessels at the same time by driving a single motor ganged to a plurality of shafts attached to agitators, in an oscillatory, rotational, or complex waveform, appropriate to the desired mixing. This embodiment provides uniform and optimal mixing to a number of separate batches or samples for experimental or small-batch production purposes.
A mixer of the present invention allows mixing with low shear forces, which is useful for cultivation of cell cultures in suspension, or because of the heavy mechanical requirements of viscous liquids.
In particular, the mixing of shear-sensitive materials, such as living animal, plant or microbial cells, e.g. with low shear forces promotes nutrient renewal at the cell surface without cell damage. Mixing with low shear forces may be achieved by use of a low-shear-inducing agitator, such as an axially driven translational agitator with frusto-conical holes therethrough, having a stroke amplitude in the range of 0.1 to 60 mm and a frequency in the range of 0.1 to 6 Hz, or optionally by a gentle, sinusoidal motion.
The invention allows for the mixing of highly viscous polymer fluids which may become either shear-thickening or shear-thinning: this is achieved by programming the controller to provide the optimal vibration frequencies and the amplitudes to minimize rising viscosity and to minimize polymer chain breakage, while still providing the desired degree of mixing for effective chemical reactions or formulations.
The invention also allows for the mixing of significantly heterogeneous formulations, such as concrete. This would be achieved by providing very large amplitude of motion to lift settled solids from deep within a mixture, and carry them to the surface to produce a homogeneous suspension.
Different from a conventional rotational mixer, embodiments of the invention that rotate the agitator can vary the instantaneous RPM in very small intervals of time and rotation such that one rotational step can be fast or slow, or forward or backwards, within broad limits. Embodiments of the invention that vibrate the agitator up and down or back and forth can vary the vibrational amplitude over a large range as well as the vibrational frequency over a large range. Frequency can vary from extremely low frequencies (Hz) to a maximum determined by the characteristics of the motor employed. Amplitude can range from as small as one step of the motor (as small as a few microns) to a maximum determined by the mechanics of the motor assembly (as large as tens of centimeters). No other mixer has this extremely wide dynamic range and high degree of programmability.
The present invention permits the use of the minimum input energy to achieve the desired result, more precise control of chemical reaction rates, and more precise control of particle size distributions and suspension homogeneity.